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Am J Respir Cell Mol Biol
Am J Respir Cell Mol Biol
ajrcmb
American Journal of Respiratory Cell and Molecular Biology
1044-1549
1535-4989
American Thoracic Society

38717817
2024-0195ED
10.1165/rcmb.2024-0195ED
Editorials
Monocytes: See One Queuing Local Adaptive Immune Responses to Respiratory Viruses
https://orcid.org/0000-0002-8015-6026
Earhart Alexander P.
https://orcid.org/0000-0003-4830-5084
Kulkarni Hrishikesh S.
John T. Milliken Department of Medicine
Washington University School of Medicine
Saint Louis, Missouri
8 5 2024
1 9 2024
8 5 2024
71 3 259261
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern.

National Heart, Lung, and Blood Institute 10.13039/100000050 K08HL148510 R01HL166449 R01HL169860 T32HL125241
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pmcThe coronavirus disease (COVID-19) pandemic has renewed focus on the host response to viral respiratory pathogens. During infection, inflammatory monocytes are recruited to produce proinflammatory mediators and are involved in the phagocytosis of virus-infected cells (1). Importantly, these monocytes facilitate antigen presentation to activate adaptive immune responses (2). Antiviral CD8+ T cells are vital to this adaptive response, as they recognize and eliminate virus-infected cells via the secretion of perforin and granzymes that induce apoptosis (3, 4). These cells also produce IFN-γ, a key antiviral cytokine that also supports the activity of other immune cells, including monocytes (5).

Another important component of the immune response to respiratory infections is the complement system (6). C1q is a vital complement protein, which together with C1r and C1s, facilitates pathogen clearance by binding to their surfaces alongside antibodies (IgG3, IgG1, IgM) and marks them for elimination (7). This process may also trigger the classical complement cascade, leading to the formation of the membrane attack complex, which disrupts viral envelopes and infected cells, helping mitigate spread (8). C1q also exerts direct effects on immune cells, as it can bind to its cognate receptor Cq1R to augment the production of proinflammatory cytokines and effector cellular function (9). However, little is known about the roles of C1q and C1qR expressed by immune cells during respiratory infections, especially how they may differentially influence innate and adaptive immunity.

In this issue of the Journal, Eddens, Parks, and colleagues (pp. 294–306) show that the response to acute human metapneumovirus (HMPV) infection requires effector CD8+ T cells, whose proper functional activation relies on a C1q-expressing inflammatory monocyte population (Figure 1) (10). The authors performed single-cell RNA sequencing analyses of HMPV-infected mouse lungs to demonstrate that inflammatory monocytes and CD8+ T cells expand during HMPV infection. Inflammatory monocytes from HMPV-infected lungs demonstrated increased C1qa, C1qb, and C1qc expression, while CellChat (http://www.cellchat.org) analysis revealed enhanced complement-related and chemokine receptor interactions, including increased communication between these inflammatory monocytes and CD8+ T cells, to induce their entry, expansion, and activation in the lungs. This study further demonstrated that the absence of C1q during HMPV infection resulted in decreased CD8+ T-cell effector function associated with a worse clinical phenotype (Figure 1). Thus, this study delineates an important role for C1q in maintaining effective adaptive immune responses during respiratory viral infection.

Figure 1. The C1q–C1qR axis is upregulated in respiratory viral infection. Infection with respiratory viruses such as human metapneumovirus results in lung inflammation, which upregulates C1q in iMono in the lung, while injury is ongoing. C1q binds to C1qR on CD8+ T cells, resulting in the upregulation of T-cell effector function, including production of granzyme B, IL-2, and IFN-γ, increasing the metabolic capacity of these cells and increasing their proliferation, subsequently resulting in viral clearance and limiting damage. This figure was created using www.biorender.com. iMono = inflammatory monocytes.

Previous work has shown that the C1q receptor, C1qR, is expressed on the surface of T cells (11). This work by Eddens, Parks, and colleagues further showed that C1q binds to C1qR, which is highly expressed on dividing effector CD8+ T cells (10). These cells expand during HMPV infection, suggesting a role for this receptor in C1q-mediated antiviral responses. In an elegant series of experiments, they also convincingly demonstrated that blocking C1qR significantly reduced IFN-γ production by CD8+ T cells even in the presence of C1q, while the frequency of granzyme B–positive cells were significantly reduced in HMPV lungs with anti-C1qR administration. Moreover, effector T-cell activity is well known to rely on enhanced mitochondrial respiratory capacity, and C1q regulates metabolic function during viral infection (9). The authors demonstrated that blocking C1qR in HMPV-infected mice decreased mitochondrial respiratory capacity in CD8+ T cells. Thus, Eddens, Parks, and colleagues provide evidence of a pivotal, although incompletely explored, mechanistic basis of how monocyte-derived C1q regulates CD8+ T-cell effector activity in the context of respiratory viral infections (10). Interestingly, a majority of C1q staining in monocytes was intracellular. The kinetics of surface expression of C1q on monocytes, the relative contributions of monocytes to C1q concentrations in BAL fluid (potentially by using conditional knockouts), and the time course of interactions between monocyte-derived C1q and C1qR on CD8+ T cells remain to be deciphered. In addition, further investigations are necessary to understand how C1q alters metabolic activity, including understanding which stage(s) of the respiratory cycles are altered by the C1q–C1qR axis. The findings of Eddens, Parks, and colleagues thus add to our understanding of how C1q acts not only to opsonize pathogens for phagocytosis but also to modulate immune responses via interactions with gC1qR to effectively help fight respiratory viral infections. They also invoke ideas that would be worthwhile exploring vis-à-vis mucosal complement responses.

It is important to note that the mouse and human immune systems are different (12, 13). Human resident alveolar macrophages produce C1q, whereas its production is limited mostly to recruited monocytes and monocyte-derived macrophages in mice (14, 15). The authors sought to address this discrepancy by examining C1q+ immunostaining in pediatric human lungs (10). Although uninfected lungs had C1q+ cells primarily within the alveoli, those from a fatal viral infection also showed diffuse C1q+ staining in cells within the interstitial and vascular space, thereby providing a human correlate to their mouse model. Interestingly, the authors also examined the expression of C1q-related genes in single-cell RNA sequencing datasets from uninfected, moderately, and severely infected patients with COVID-19. They showed that uninfected patients expressed C1q primarily in alveolar macrophages, whereas the majority of C1q expression in patients with COVID-19 was in recruited monocytes and macrophages, including interstitial macrophages (10). As with their findings in mice, the authors also pinpointed expression of the human C1qR gene, C1QBP, to the expanding CD8+ T-cell population in infected patients, which was significantly more pronounced in those with severe COVID-19. These findings suggest that their animal modeling may be a valuable surrogate for human respiratory viral infections. Their translation would be aided by functional experiments investigating targeted immunosuppression to prevent potentially detrimental immunopathology or antagonizing C1qR to further validate its role in human effector CD8+ T cells. However, controlled immunomodulatory experiments are difficult to perform in human respiratory infections, given that patients present at variable times after symptom onset. To overcome these limitations, humanized mouse models could be used to further examine functionality of these dividing CD8+ T cells in the presence or absence of C1q or antagonizing gC1qR. Such work could help fast-track clinical trials of complement therapeutics for potentially fatal respiratory viral infections.

In summary, this study by Eddens, Parks, and colleagues (10) makes an important contribution to our understanding of how complement component C1q directly acts on immune cells to combat respiratory viral pathogens, while it also adds to the body of work examining how the complement system lies at the intersection between innate and adaptive immunity. This work also further opens the possibility of using complement-based therapies, especially those optimally modulating C1q, to help tackle infections by such pathogens. Interestingly, it also suggests that, in some cases, therapeutic blocking of gC1qR may alleviate potentially fatal immunopathologic outcomes, as certain deaths due to respiratory viral infections (e.g., in severe COVID-19) can be attributed to hyperresponsiveness of the immune system.

Supported by National Institutes of Health grants T32HL125241 (A.E.), R01HL166449 , and R01HL169860 and National Heart, Lung, and Blood Institute grant K08HL148510 .

Originally Published in Press as DOI: 10.1165/rcmb.2024-0195ED on May 8, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
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